The medicinal chemistry of multidrug resistance (MDR) reversing drugs

Teodori, Elisabetta; Dei, Silvia; Scapecchi, Serena; Gualtieri, Fulvio

doi:10.1016/s0014-827x(02)01229-6

Cited by 159 publications

(124 citation statements)

References 255 publications

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“…As a consequence, the clinical utility of non-toxic derivatives of these and other molecules as chemosensitizing agents has been extensively studied. 10,11) It was reported that in MDR plasmodium falciparum strains, the pfmdr-1 gene and pgh-1 were characterized, which has about 54% homology to mdr-1 gene of MDR cancer cells. [12][13][14][15] However, its function is still not clear.…”

mentioning

confidence: 99%

Modulation of Multidrug Resistance by Artemisinin, Artesunate and Dihydroartemisinin in K562/adr and GLC4/adr Resistant Cell Lines.

Reungpatthanaphong

Mankhetkorn

2002

Biological & Pharmaceutical Bulletin

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Multidrug resistance (MDR) is a principle cause of failure in human drug treatment. MDR phenomena are intensively studied in anti-cancer, anti-bacterial, anti-paludism, and human immunodeficiency virus-1. [1][2][3][4][5] The MDR phenotype is characterized by a low free intracellular cytotoxic drug concentration in comparison with their corresponding drugsensitive cells. This is frequently associated with protein membrane transporters, such as P-glycoprotein and MRP1-protein, which ATP-dependently extrude cytotoxic agents out of cells, thus reducing their efficacy. To overcome MDR phenomena, the direct interaction between inhibitors and proteins has been researched by many groups. A variety of small molecules, such as verapamil, dihydropyridines, forskolin and cyclosporin were found to bind to P-glycoprotein and inhibit its ability to pump out antitumor drugs. 6-9) All compounds cited are difficult to use in vivo due to their toxicity. As a consequence, the clinical utility of non-toxic derivatives of these and other molecules as chemosensitizing agents has been extensively studied. 10,11) It was reported that in MDR plasmodium falciparum strains, the pfmdr-1 gene and pgh-1 were characterized, which has about 54% homology to mdr-1 gene of MDR cancer cells. [12][13][14][15] However, its function is still not clear. Recently, it was reported that qinghaosu is an effective compound against MDR plasmodium falciparum strains, 16,17) but studies regarding its effect on protein transporters have not been performed, neither in erythrocytes infected by MDR plasmodium falciparum strains nor in cancer MDR cells. Qinghaosu drugs such as artemisinin and artesunate are now in widespread use, particularly in Southast Asia, and are used as a prophylaxis in China. 18,19) In this study we have demonstrated that artemisinin, artesunate and dihydroartemisinin poorly inhibited P-glycoprotein and did not inhibit MRP1 protein function in multidrug resistant K562/adr cells, overexpression P-glycoprotein, or in GLC4/adr cells overexpression of MRP1-protein, respectively. However, they increased in cytotoxic effect induced by pirarubicin or doxorubicin only in MDR cell lines. We also demonstrated that these qinghaosu modulate mitochondrial function, leading to a decrease in intracellular ATP content in all cell lines tested. MATERIALS AND METHODS Cell Culture and Cytotoxicity AssayThe erythromyelogenous leukemic, K562, and its P-glycoprotein-overexpressing K562/adr, 20,21) and the human small cell lung cancer, GLC4 and its MRP1-overexpressing GLC4/adr, [22][23][24] were kindly provided by Professor Arlette Garnier-Suillerot, Laboratoire de Chimie Physique, Biomoleculaire et Cellulaire, UFR Sante Medecine Biologie Humaine, Universite de Paris Nord, France. These cells were routinely cultured in RPMI 1640 medium supplemented with 10% fetal calf serum (Gibco Biocult, Ltd.). The resistant K562/adr and GLC4/adr cells were cultured with 100 nM doxorubicin two weeks before the experiments. For the assays, a culture was initiated at 5ϫ10 5 cells ...

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confidence: 99%

Modulation of Multidrug Resistance by Artemisinin, Artesunate and Dihydroartemisinin in K562/adr and GLC4/adr Resistant Cell Lines.

Reungpatthanaphong

Mankhetkorn

2002

Biological & Pharmaceutical Bulletin

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“…Parental cells (Tca8113) and the chemotherapy resistant cell lines (Tca8113/CBP and Tca8113/PYM) were seeded at a density of 5x10 4 cells/well in 6-well plates containing preplaced coverslips and grown for 72 h. The coverslips were fixed in 4% paraformaldehyde for 30 min, followed by 0.25% Triton X-100 (Amresco, LLC, Solon, OH, USA) for 15 min. Next, the samples were treated with 3% H 2 O 2 for 30 min and rinsed three times in phosphate buffered saline (PBS; pH 7.4) for 5 min each time.…”

Section: Drugsmentioning

confidence: 99%

“…Therefore, drug accumulation in the cells is reduced and MDR is increased. Upon the development of MDR, tumor cells are resistant to multiple chemotherapeutic drugs and reversing this process is difficult (4,5). A number of researchers have attempted to design novel approaches in order to monitor the development of MDR throughout the chemotherapeutic process (3,6,7).…”

Section: Introductionmentioning

confidence: 99%

1H nuclear magnetic resonance-based extracellular metabolomic analysis of multidrug resistant Tca8113 oral squamous carcinoma cells

et al. 2015

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Abstract.A major obstacle of successful chemotherapy is the development of multidrug resistance (MDR) in the cancer cells, which is difficult to reverse. Metabolomic analysis, an emerging approach that has been increasingly applied in various fields, is able to reflect the unique chemical fingerprints of specific cellular processes in an organism. The assessment of such metabolite changes can be used to identify novel therapeutic biomarkers. In the present study, 1 H nuclear magnetic resonance (NMR) spectroscopy was used to analyze the extracellular metabolomic spectrum of the Tca8113 oral squamous carcinoma cell line, in which MDR was induced using the carboplatin (CBP) and pingyangmycin (PYM) chemotherapy drugs in vitro. The data were analyzed using the principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) methods. The results demonstrated that the extracellular metabolomic spectrum of metabolites such as glutamate, glycerophosphoethanol amine, α-Glucose and β-Glucose for the drug-induced Tca8113 cells was significantly different from the parental Tca8113 cell line. A number of biochemicals were also significantly different between the groups based on their NMR spectra, with drug-resistant cells presenting relatively higher levels of acetate and lower levels of lactate. In addition, a significantly higher peak was observed at δ 3.35 ppm in the spectrum of the PYM-induced Tca8113 cells. Therefore, 1 H NMR-based metabolomic analysis has a high potential for monitoring the formation of MDR during clinical tumor chemotherapy in the future.

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“…Intensive screening efforts have led to the discovery of highly promising marine natural product-based anti-MDR compounds that have been evaluated in clinical studies [268,269]. Compounds such as verapamil, dexverapamil and other anti-MDR inhibitors have been introduced into clinical trials, only to be dropped because of toxicity.…”

Section: Multidrug Effluxmentioning

confidence: 99%

Mechanism Targeted Discovery of Antitumor Marine Natural Products

Nagle¹,

Zhou²,

Mora³

et al. 2004

Current Medicinal Chemistry

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Antitumor drug discovery programs aim to identify chemical entities for use in the treatment of cancer. Many strategies have been used to achieve this objective. Natural products have always played a major role in anticancer medicine and the unique metabolites produced by marine organisms have increasingly become major players in antitumor drug discovery. Rapid advances have occurred in the understanding of tumor biology and molecular medicine. New insights into mechanisms responsible for neoplastic disease are significantly changing the general philosophical approach towards cancer treatment. Recently identified molecular targets have created exciting new means for disrupting tumor-specific cell signaling, cell division, energy metabolism, gene expression, drug resistance, and blood supply. Such tumor-specific treatments could someday decrease our reliance on traditional cytotoxicity-based chemotherapy and provide new less toxic treatment options with significantly fewer side effects. Novel molecular targets and state-of-the-art molecular mechanism-based screening methods have revitalized antitumor research and these changes are becoming an ever-increasing component of modern antitumor marine natural products research. This review describes marine natural products identified using tumor-specific mechanism-based assays for regulators of angiogenesis, apoptosis, cell cycle, macromolecule synthesis, mitochondrial respiration, mitosis, multidrug efflux, and signal transduction. Special emphasis is placed on natural products directly discovered using molecular mechanism-based screening.

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The medicinal chemistry of multidrug resistance (MDR) reversing drugs

Cited by 159 publications

References 255 publications

Modulation of Multidrug Resistance by Artemisinin, Artesunate and Dihydroartemisinin in K562/adr and GLC4/adr Resistant Cell Lines.

Modulation of Multidrug Resistance by Artemisinin, Artesunate and Dihydroartemisinin in K562/adr and GLC4/adr Resistant Cell Lines.

1H nuclear magnetic resonance-based extracellular metabolomic analysis of multidrug resistant Tca8113 oral squamous carcinoma cells

Mechanism Targeted Discovery of Antitumor Marine Natural Products

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